Somatostatin an agent that inhibits glucagon and insulin secretion, was utilized to evaluate the relative roles of insulin and glucagon in diabetes. The effect of prolonged somatostatin infusion on fasting hyperglycemia in maturity-onset diabetes and the effect of glucagon replacement on the blood glucose response to somatostatin in normal man was determined. In maturity-onset diabetics, somatostatin only transiently lowered blood glucose. After 5 hours plasma glucose levels rose to levels 45-50mg percent above saline control value (P less than 0.001) despite suppression of plasma glucagon. In addition somatostatin accentuated diabetic hyperketonemia and hyperaminoacidemia. The addition of replacement doses of glucagon failed to exaggerate the late hyperglycemic effects of prolonged insulin suppression induced by somatostatin. These findings indicate the primary role of insulin deficiency rather than glucagon excess in the pathogenesis of diabetes and the potentially deleterious effects of somatostatin in treating diabetics with residual insulin secretion. Studies in dogs indicate that prolonged infusions of glucagon and epinephrine produce only transient stimulation of hepatic glucose production. However, hepatic unresponsiveness to persistent elevations of glucagon or epinephrine is specific for the particular hormone administered inasmuch as a prompt increase in hepatic glucose output is observed when the other hormone is given. Additional studies suggest that somatostatin directly alters the in vivo hepatic response to physiologic increments in glucagon or epinephrine. Somatostatin potentiates the stimulatory effects of glucagon on glucose production independent of insulin availability and blunts the stimulatory effects of epinephrine independent of glucagon availability. Finally, our data indicate that basal insulin secretion is an important regulator of normal potassium homeostasis. Acute insuline deficiency induced by somatostatin causes a rise in serum potassium and a decrease in potassium tolerance.